Population studies have demonstrated that the prevalence and incidence of coronary heart disease is inversely correlated with the plasma concentration of high density lipoprotein (HDL) cholesterol, suggesting that HDL may protect against atherosclerosis. This protection may be related to the ability of HDL to promote the "clearance" of cholesterol from cells of the artery wall. In support of this proposal are results from recent studies suggesting that cultured extrahepatic, nonsteroidogenic cells possess specific high-affinity receptors on their cell surfaces that are induced when cells become loaded with cholesterol. More recent studies have identified a 75,000- to 80,000- molecular-weight protein in membranes from cholesterol-loaded cells that appears to be the HDL receptor. The objective of this research proposal is to characterize the physical and biochemical properties of this receptor and its attendant cellular pathway and to assess the role of this receptor in modulation of cellular cholesterol homeostasis in cells of the artery wall. Studies are proposed to isolate and purify the receptor protein and to characterize its properties. With the use of technology in areas of cell biology, molecular biology, and immunochemistry, the cellular pathway for synthesis, processing, and transporting of HDL receptors and its ligands will be studied. In addition, studies will be designed to identify and define possible genetic polymorphisms in the structure of HDL apoproteins and the HDL receptor that could lead to defective receptor-ligand interaction and abnormal cellular cholesterol metabolism. Results from these studies should increase our understanding of the role of HDL in modulation of cholesterol content of the artery and provide insights into possible biochemical and genetic defects that contribute to the pathogenesis of atherosclerosis.